The Wild-Type NF1 Gene: It's a Real Turnoff.

From the Department of Ophthalmology, NYU Langone Medical Center, Bellevue Hospital Center, and Manhattan Eye, Ear and Throat Hospital, New York, New York. The author has no financial or proprietary interest in the materials presented herein. Correspondence: Anna Escuder, MD, Department of Ophthalmology, NYU Langone Medical Center, 462 First Avenue, NBV 5N1-6, New York, NY 10016. E-mail: [email protected] doi:10.3928/01913913-20170706-01 Neurofibromatosis type 1 (NF1) is one of the most common autosomal-dominant inherited syndromes, affecting 1 in 3,000 to 3,500 people with a wide range of clinical manifestations and disease severity. Friedrich Daniel Von Recklinghausen first described its features in 1882. Most importantly, the hallmark of NF1 is the development of multiple benign tumors of the peripheral nervous system with an increased risk of malignancies. Underlying the clinical manifestations of NF1 are its unique genetics and the pathophysiology of the disease. The NF1 gene was identified in 1990. By genetic linkage analysis of families with multiple affected members, the gene was mapped to chromosome 17q11.2. Balanced translocations that produced NF1 were isolated in hybrid cell lines from two unrelated individuals, and breakpoints were physically mapped 55 kb apart in the same region identified by the genetic mapping. Genomic DNA mapping to this region provided probes to identify clones from complementary DNA libraries. Of the four genes found at this locus, mutations in genomic DNA from affected individuals consistently involved only one of the four genes, thereby identifying the NF1 gene. This NF1 gene encodes for a 2818 amino acid peptide (the neurofibromin protein). Neurofibromin functions as a tumor suppressor and is expressed predominantly in neurons and glial and Schwann cells. The fundamental mechanism of tumor formation in NF1 is connected to the oncogene Ras. Ras encodes a family of GTPase proteins that are ubiquitously expressed in all cell lines and organs. This protein family is involved in cell growth, differentiation, and survival. However, when overexpressed or uncontrolled, this protein family also leads to cancer formation. The central domain of the neurofibromin protein is homologous to Ras GTPase activating proteins (GAPs), which convert Ras into its inactive form, thus suppressing cell growth. Ras has two conformational states: active when GTP-bound and inactive when GDP-bound. Neurofibromin switches Ras to the inactive GDP-bound state. Thus, the loss of the normal function of neurofibromin in NF1 results in loss of Ras suppression, subsequently leading to cell proliferation. This uncontrolled cell growth underlies the predisposition to developing plexiform The Wild-Type NF1 Gene: It’s a Real Turnoff